ABSTRACT Genetic and genomic investigations have yielded important findings as to the genetic contributions to major psychiatric illnesses, illustrating significant etiological heterogeneity, as well as cross-disorder overlap. It has also become clear that understanding how this genetic variation leads to alterations in brain development and function that underlies psychiatric disease pathophysiology will be greatly advanced by a roadmap of the transcriptomic and epigenetic landscape of the human cerebral cortex across key developmental windows. Here, we propose, via a highly collaborative group of investigators, each with distinct areas of expertise and research focus, to create a scaffold of genomic data for understanding ASD pathophysiology, and psychiatric disorders more broadly. The work proposed here represents an ambitious multi-PI project (Yale, UCLA, and UCSF) that brings together three principal investigators and collaborators with strong publication records and expertise in all approaches necessary to perform this work using state-of-the-art and novel methodologies. We will perform time-, region-, and cell type-specific molecular profiling of control and ASD brains (Aim 1), including RNA-seq based transcriptomics, identifying cis-regulatory elements via ChIP-seq, and use Hi-C to determine the 3D chromatin architecture and physical relationships that underlie transcriptional regulation in three major regions implicated in neuropsychiatric disease (frontal and temporal cortex and striatum) across five major epochs representing disease-relevant stages in human brain development. This will include complementary genomic analyses in controls and matched post mortem ASD brain to identify genetic mechanisms underlying processes altered in ASD brain. We will address cellular heterogeneity via fluorescence-activated nuclear sorting (FANS) so as to profile neurons and non-neural cells separately, which will complement the whole tissue analyses. We will analyze and integrate these datasets to identify regional, developmental, and ASD-related processes to gain insight into underlying mechanisms, harmonizing these multi-omic data with other psychENCODE studies, as well as other large scale data sets, such as BrainSpan, ENCODE, GTEx and Roadmap Epigenomics Project (Aim 2). We will perform integrated analysis of germ-line ASD variations identified in more than 1000 families from the Simons Simplex Collection to characterize causal enrichments in developmental periods, brain regions, and cell types to better characterize the mechanisms by which genetic variation in humans alters brain development and function in health and disease (Aim 3). Completion of these aims will lead to a well-integrated resource across major periods in human cortical and striatal development that will permit generation of concrete testable hypotheses of ASD mechanisms, and inform our pathophysiological understanding of other related neuropsychiatric disorders.